Process for the synthesis of ribonucleotide reductase inhibitors 3-AP and 3-AMP

Abstract

The present invention relates to improved, efficient chemical syntheses of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) and 3-amino-4-methylpyridine-2-carboxaldehyde thiosemicarbazone (3-AMP).

We claim: 
     
       1. A method for producing a compound of the formula: ##STR3## where R 1  is NO 2 , NH 2 , NHP, NPP', N 3  or CO 2  R 2  ; P and P' are protecting groups;   R 2  is Me,Et, Pr or I--Pr; and   R 4  is H or CH 3     comprising subjecting a compound of the formula: ##STR4## where R is Cl, Br, I, OMs, OTf or OTs;   R 1  is NO 2 , NH 2 , NHP, NPP', N 3  or CO 2  R 2  ;   P and P' are protecting groups;   R 2  is Me,Et, Pr or I--Pr; and   R 4  is H or CH 3   to a vinylation reaction to produce a compound according to the formula: ##STR5## where R 1  is NO 2 , NH 2 , NHP, NPP', N 3  or CO 2  R 2  ;     P and P' are protecting groups;   R 2  is Me,Et, Pr or I--Pr; and   R 3  is H, C 1  to C 20  alkyl, aryl, substituted aryl or CO 2  R 2  ; and   R 4  is H or CH 3  ; and then subjecting compound 2-VP to ozonolysis to produce compound 2-C.     
     
     
       2. The method according to claim 1 wherein R is Cl, Br or I and R 1  is NO 2 . 
     
     
       3. The method according to claim 1 wherein R 3  is H. 
     
     
       4. The method according to claim 1 wherein R 3  is a phenyl group. 
     
     
       5. The method according to claim 1 wherein R 4  is H. 
     
     
       6. The method according to claim 1 wherein R 4  is CH 3 . 
     
     
       7. The method according to claim 1 wherein R 1  is NO 2 . 
     
     
       8. The method according to claim 1 wherein R 1  is NH 2 . 
     
     
       9. The method according to claim 1 wherein R is OMs, OTs or OTf. 
     
     
       10. A method of producing a compound of formula 4: ##STR6## comprising reacting a compound according to a formula 3: ##STR7## with dimethylformamidedialkylacetal to form a compound according to formula 3a: ##STR8## and then reacting said compound 3a with an oxidizing agent to form compound 4, said compound 4 being isolated in at least 75% yield from said compound 3. 
     
     
       11. The method according to claim 10 wherein said dimethylformamidedialkylacetal is dimethylformamidedimethylacetal. 
     
     
       12. The method according to claim 10 wherein said oxidizing agent is sodium periodate.